Effects of Ghrelin Administration on Dopamine and Effort

Ghrelin is a stomach-derived hormone and the only known circulating peptide that stimulates appetite. Animal studies have conclusively shown that ghrelin increases dopaminergic neurotransmission and, thereby, enhances effort. However, similar evidence on the putative role of ghrelin in humans is still lacking. Here, the investigators propose to conduct a [11C]-raclopride PET/MR study after intravenous administration of ghrelin vs. saline in healthy individuals. First, during an intake visit, the investigators will assess fasting blood levels of hormones involved in appetitive behavior such as ghrelin, leptin, and insulin. In addition, the investigators will conduct a set of tasks that have been associated with dopamine function (i.e., effort and reinforcement learning). Second, the investigators will assess the effects of intravenous administration of ghrelin on dopamine signaling using a double-blind randomized cross-over design. To this end, participants will be infused with ghrelin (vs. saline) while we determine dopamine release (via PET imaging) and assess cerebral blood flow and functional connectivity at rest (via concurrent MR imaging). Furthermore, the investigators will conduct an instrumental motivation task (IMT) where participants have to exert physical effort to obtain rewards. Based on preclinical studies and indirect evidence from human studies, the investigators hypothesize that ghrelin will increase dopamine release in the striatum and that this will, in turn, lead to an increase in the willingness to work for rewards. Moreover, the investigators expect that ghrelin-induced dopamine release will be associated with an elevated tracking of reward utility in the mesolimbic circuit during the IMT, which is known to be associated with response vigor. Collectively, the proposed project would provide a unique resource to test an important link between the gut and the brain in the regulation of appetitive behavior. If ghrelin were to enhance effort expenditure for rewards via dopamine signaling in humans, then restoring sensitivity to ghrelin might be the more promising therapeutic approach compared to antagonizing the ghrelin receptor.

The investigators will assess the effects of intravenous administration of ghrelin on dopamine signaling using a double-blind randomized cross-over design. To this end, 26 healthy participants will be infused with ghrelin (vs. saline) while we determine dopamine release (via PET imaging) and assess cerebral blood flow and functional connectivity at rest (via concurrent MR imaging). These 26 healthy participants will be drawn from a larger sample of 100 participants (including 50 patients with major depressive disorders), who will complete a reward task battery that will be associated with fasting blood levels of ghrelin.

Neither participants nor investigators will know whether the participant receives a ghrelin or saline infusion, which will be prepared by independent members of the university hospital.

To achieve approximately stable elevated ghrelin levels during the infusion procedure, the investigators will use a loading dose of 1 mcg/kg as well as an infusion rate of 0.051 mcg/kg/min in line with recent studies (Farokhnia, Grodin, Lee et al., 2017) and general recommendations (Garin, Burns, Kaul et al., 2013).

Patients with major depressive disorder will be enrolled for comparison to healthy participants on the reward task battery, but not randomized to the ghrelin vs. saline infusion.

Participants will receive an infusion that is intended to raise ghrelin level up to a steady plateau.

Functional connectivity and perfusion of regions of the reward circuit (i.e., Nucleus Accumbens and Ventral Tegmental Area/Substantia Nigra) after ghrelin infusion vs. saline infusion

Change in visual analogue scale (0-100) measures of subjective hunger and satiety after ghrelin infusion vs. saline infusion

Changes operationalized via visual analogue ratings (0-100) of positive and negative affect schedule mood items after ghrelin infusion vs. saline infusion

Inclusion Criteria: Healthy control participants: never fulfilled the criteria of any mood or anxiety disorder (except specific phobia) Patients with major depressive disorder: diagnosis according to DSM-5 within 12 months before enrollment and presence of at least mild symptoms at enrollment (BDI II >= 14) Exclusion Criteria: lifetime history of a brain injury, schizophrenia, bipolar disorder, and a severe substance use disorder according to DSM-5 obsessive-compulsive disorder, trauma- and stressor-related disorder, somatic symptom disorder, and eating disorder within a 12-month interval before the test day. Neuroimaging Study involving ghrelin infusion: contraindication for PET/MR (e.g., metal implants or prostheses, pregnancy, claustrophobia)

After the publication of the key results of the study, all anonymized imaging data will be made publicly available (e.g., at openfmri.org). Behavioral data will be shared after aggregation at the trial or participant level.